EP1062358B1 - Nouveau procede de preparation de la fexofenadine - Google Patents
Nouveau procede de preparation de la fexofenadine Download PDFInfo
- Publication number
- EP1062358B1 EP1062358B1 EP99909036A EP99909036A EP1062358B1 EP 1062358 B1 EP1062358 B1 EP 1062358B1 EP 99909036 A EP99909036 A EP 99909036A EP 99909036 A EP99909036 A EP 99909036A EP 1062358 B1 EP1062358 B1 EP 1062358B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- streptomyces
- compound
- fexofenadine
- triol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229960003592 fexofenadine Drugs 0.000 title claims abstract description 46
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 36
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229960000351 terfenadine Drugs 0.000 claims abstract description 39
- 241000144128 Lichtheimia corymbifera Species 0.000 claims abstract description 27
- 229910019142 PO4 Inorganic materials 0.000 claims description 31
- 239000010452 phosphate Substances 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 230000009466 transformation Effects 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 241000593945 Streptomyces platensis Species 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 241000187747 Streptomyces Species 0.000 claims description 12
- 244000005700 microbiome Species 0.000 claims description 12
- 239000001963 growth medium Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000005273 aeration Methods 0.000 claims description 3
- 230000036983 biotransformation Effects 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000009631 Broth culture Methods 0.000 claims 1
- 238000011534 incubation Methods 0.000 description 36
- 239000002609 medium Substances 0.000 description 32
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000002028 Biomass Substances 0.000 description 10
- 239000012153 distilled water Substances 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 10
- 241001459306 Lichtheimia blakesleeana Species 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000002906 microbiologic effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000010633 broth Nutrition 0.000 description 3
- AIUDWMLXCFRVDR-UHFFFAOYSA-N dimethyl 2-(3-ethyl-3-methylpentyl)propanedioate Chemical compound CCC(C)(CC)CCC(C(=O)OC)C(=O)OC AIUDWMLXCFRVDR-UHFFFAOYSA-N 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000235389 Absidia Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000235555 Cunninghamella Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000186984 Kitasatospora aureofaciens Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000187559 Saccharopolyspora erythraea Species 0.000 description 2
- 241000187759 Streptomyces albus Species 0.000 description 2
- 241000187758 Streptomyces ambofaciens Species 0.000 description 2
- 241000186988 Streptomyces antibioticus Species 0.000 description 2
- 241000970256 Streptomyces djakartensis Species 0.000 description 2
- 241000520732 Streptomyces felleus Species 0.000 description 2
- 241000187438 Streptomyces fradiae Species 0.000 description 2
- 241000187392 Streptomyces griseus Species 0.000 description 2
- 241000187398 Streptomyces lividans Species 0.000 description 2
- 241000946831 Streptomyces narbonensis Species 0.000 description 2
- 241000218589 Streptomyces olivaceus Species 0.000 description 2
- 241000187419 Streptomyces rimosus Species 0.000 description 2
- 241000531819 Streptomyces venezuelae Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000013256 coordination polymer Substances 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 240000005007 Actinomucor elegans Species 0.000 description 1
- 235000013650 Actinomucor elegans Nutrition 0.000 description 1
- 244000251953 Agaricus brunnescens Species 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000122824 Aspergillus ochraceus Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- SRLLQDNDXGMTBP-UHFFFAOYSA-N C(C)#N.O.OC(=O)C(F)(F)F.FC(C(=O)O)(F)F Chemical group C(C)#N.O.OC(=O)C(F)(F)F.FC(C(=O)O)(F)F SRLLQDNDXGMTBP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000010216 Cunninghamella blakesleeana Species 0.000 description 1
- 241001290628 Cunninghamella echinulata Species 0.000 description 1
- 241000235556 Cunninghamella elegans Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- RRJFVPUCXDGFJB-UHFFFAOYSA-N Fexofenadine hydrochloride Chemical compound Cl.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RRJFVPUCXDGFJB-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000010364 biochemical engineering Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960000354 fexofenadine hydrochloride Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
Definitions
- the subject of the present invention is a new process for preparation of Fexofenadine.
- Fexofenadine is a drug that has significant antihistamine activity and that has no side effects. (Efficacy and safety of Fexofenadine hydrochloride for treatment of seasonal allergic rhinitis, Bernstein DI et al, Ann. Allergy-Asthma-Immunol. (1997) 79 (5) 443-448.
- Terfenadine itself antihistamine agent (D. Mc Tavish, KL Goa and M. Ferill, "terfenadine: an updated review of its pharmacological properties and therapeutic efficiency, Drug 39, 552-574 (1989)).
- Fexofenadine is currently being prepared chemical, in many stages with lower yield at 10% (US Patents 5,578,610 and 5,581,011).
- Application EP-A-864 653 describes a microbiological transformation process from Terfenadine to Fexofenadine using either Cunninghamella or Absidia as a strain .
- the subject of the invention is a process for the preparation of the compounds of formula (I): characterized in that a bioconversion of the compound or compounds of formula (II) is carried out: with either a culture of a microorganism of the genus Absidia corymbifera, or a culture of a microorganism of the genus Streptomyces, at a pH between 5.0 and 8.0, in order to obtain the compound or compounds of formula (I) expected, which if necessary are isolated, purified and / or salified, the compounds of formulas (I) or (II) possibly being in the two possible enantiomeric forms, isolated or in mixtures.
- the asterisk indicates the position of the asymmetric carbon.
- the invention particularly relates to a preparation process as described above in which the Absidia c orymbifera is Absidia corymbifera LCP 63-1800 or in which the Streptomyces is Streptomyces platensis NRRL 2364.
- Fexofenadine is a racemic mixture of enantiomers of formula (I).
- the process therefore has more particularly for object the method as described above in which we carry out a bioconversion of Terfenadine, corresponding to a racemic mixture of the two enantiomers of formula (II), in order to obtain Fexofenadine, corresponding to a racemic mixture of the enantiomers of formula (I).
- Absidia corymbifera and in particular Absidia corymbifera LCP 63-1800 are available at the Cryptogamy Laboratory of the Museum of Natural History in Paris.
- the possible purification step is basically only to eliminate a secondary product which can be formed during bioconversion, namely the triolphosphate which corresponds to alcohol not yet oxidized to acid, esterified in the form of a phosphate (formula (IIIb)) described below.
- the purification is carried out according to the known methods of the skilled person. It can be a purification by crystallization, by chromatography or by exchange resin ion.
- Salification reactions can be carried out under usual conditions. We operate for example in presence of ethanolic soda. You can also use a sodium salt such as carbonate or acid carbonate of sodium or potassium.
- the salts obtained can be alkali or alkaline earth or ammonium salts possibly substituted.
- the oxidation is carried out according to the commonly used methods for microbiological oxidation organic molecules using cultures of filamentous fungi (Holland HL, Organic synthesis with oxidative enzymes. VCH publisher, Inc, New York 1992; Lacroix I, Biton J and Azerad R, Microbial biotransformation of a synthetic immunomodulating agent HR325, Bioorg. Med. Chem. (1997) 7, 1369-1380; Sebek OK, Fungal transformations as a useful method for the organic synthesis of organic compounds, Mycologia 75 (2) 383-394, 1983 Azerad, R. Microbial models for drug metabolism, Advances in Biochemical Engineering and Biotechnology, Vol. 63, page 169, 1999.
- the fermentation conditions more favorable, such as the choice of environment nutrient, appropriate substrate solvent, concentration substrate, technical conditions such as temperature, ventilation, pH, and optimum periods for culture, addition of substrate and contact of substrate with the microorganism.
- the culture is carried out from an inoculum (spores or mycelium) of Absidia corymbifera LCP 63-1800 or from a bacterium of the genus Streptomyces, in particular Streptomyces platensis NRRL 2364, in a liquid nutritive medium with an initial pH of 5 to 7 and at a temperature of 20 to 30 ° C, preferably from 26 to 28 ° C.
- Aeration is ensured by rotary agitation of the culture vessels (150 to 250 rpm) or, in a fermenter, by introduction of air at a flow rate of approximately 1 l / min and per liter of culture broth.
- terfenadine is added to a concentration from 0.1 to 1 g / liter, preferably 0.4 to 0.6 g / liter, in solution in an organic solvent miscible with water, such as ethanol, acetone, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide (5 to 20 ml / liter of culture), preferably ethanol (10 ml / liter).
- an organic solvent miscible with water such as ethanol, acetone, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide
- PH is eventually readjusted and kept at a value of 5.0 to 8.0.
- the transformation of the substrate is advantageously monitored by HPLC analysis of the incubation supernatant or chromatography as a thin layer of samples extracted by a organic solvent. In general after 48 to 200 hours, it has formed sufficient amounts of exofenadine.
- Another procedure is to separate the biomass from the culture medium by filtration, wash with water or buffered solution of neutral pH, then put it back suspension in a suitable buffer, for example a buffer 0.05 M phosphate at pH 7, then add the substrate and continue the incubation as described above.
- a suitable buffer for example a buffer 0.05 M phosphate at pH 7, then add the substrate and continue the incubation as described above.
- Isolation and purification of process products are carried out in a manner known per se.
- a solvent organic preferably ethyl acetate
- a hydrophobic column followed by elution with a organic solvent, evaporate the organic solvent, separate and purify the products by column chromatography or by crystallization.
- One of the objectives of the invention is to adjust the pH to during the incubation and possibly keep it at a optimized value, in order to minimize the formation of secondary products.
- Terfenadine (II) into Fexofenadine (I) by A. corymbifera or S. platensis involves several successive stages, with the intermediate formation of triol (IIIc) and that of two unwanted secondary products, Terfenadine phosphate (IIIa) and the triolphosphate (IIIb) according to the diagram below:
- the invention also relates to intermediate compound, the compound of formula (IIIc), such as defined above.
- 250 ml erlens containing 100 ml of culture medium are inoculated with a suspension of freshly harvested spores on solid medium and growth is carried out in a rotary incubator at 27 ° C and 200 RPM for 66 hours.
- Terfenadine is added in solution in ethanol (10 ml / liter) at a final concentration of 0.2 g / l directly to biomass in its culture medium.
- terfenadine (II) has a retention time of 14.56 min., terfenadine-P (IIIa), a retention time of 11.8 min., triol (IIIc), a retention time of 9.61 min., fexofenadine, a retention time of 9.45 min. and triol-P (IIIb), a retention time of 7.43 min.
- the culture of Absidia corymbifera is carried out in medium A (pH 6.5), but in a Biolafitte fermenter, in a volume of 5 liters inoculated with 2.10 6 spores / liter, at 27 ° C, with an air flow of 5 liters / min approximately and agitation (helical turbine) of 275 revolutions / min.
- the biomass obtained after 66 hours of culture and which is in the form of homogeneous pellets of about 1 mm in diameter was used for bioconversion directly in the culture fermenter. 1.25 g of Terfenadine in 50 ml of ethanol are added and the incubation is continued under the same conditions for 7 days.
- the pH is 8.5 and the incubation medium contains 35% fexofenadine and 65% triolphosphate.
- the biomass is separated from the liquid medium by filtration.
- the filtrate is saturated with NaCl, its pH is adjusted to 6.0 with dilute HCl and it is extracted 3 times with ethyl acetate.
- 350 mg (27%) of pure fexofenadine are recovered.
- the triolphosphate (IIIb) can be recovered in the aqueous phase by adsorption on a column of XAD-2 and elution with methanol.
- the culture of Absidia corymbifera is carried out in medium D (pH 6.5), in a Biolafitte fermenter, under the same conditions as in Example 3.
- the biomass obtained after 66 hours of culture is used for bioconversion directly in the culture fermenter.
- 1 g of Terfenadine in 25 ml of ethanol are added and the incubation is continued under the same conditions for 4 days.
- the pH is 8.0 and the incubation medium contains 70% fexofenadine and 30% triolphosphate which are isolated and purified as described in Example 3.
- the culture of Absidia corymbifera is carried out in medium D (pH 6.5), under the conditions described in Example 3.
- 2.5 g of Terfenadine in 50 ml of ethanol are added and the incubation is continued in the same conditions for 4 days.
- the pH is 8.0 and the incubation medium contains 42% fexofenadine, 13% triol (IIIc) and 25% triolphosphate (IIIb).
- the pH is adjusted to 3.5 with concentrated HCl and the incubation is continued under the same conditions, allowing the pH of the medium to evolve freely up to 6 (3 days).
- the triol phosphate (IIIb) has almost completely disappeared in favor of the triol.
- the pH is readjusted to 8.0 and the incubation is continued under the same conditions for a further 2 days.
- the medium then contains 85% fexofenadine and 13% triol phosphate (IIIb).
- the culture of Absidia corymbifera is carried out in medium D (pH 6.5), under the conditions described in Example 3.
- 2.5 g of Terfenadine in 50 ml of ethanol are added and the incubation is continued in the same conditions for 4 days.
- the pH is 8.0 and the incubation medium contains 35% fexofenadine, 11.5% triol (IIIc) and 34% triolphosphate (IIIb).
- the pH is adjusted and maintained at 6.0-6.5 with dilute HCl while the incubation is continued under the same conditions (3 days).
- the medium then contains 89.5% fexofenadine and 9.5% triol phosphate.
- a 250 ml Erlenmeyer flask containing 100 ml of medium E is inoculated with Streptomyces platensis NRRL 2364 and cultured as described in Example 1.
- Half of the culture medium and the biomass, the pH of which is 5.0, is supplemented with 10 mg of terfenadine dissolved in 0.5 ml of ethanol and the incubation is continued for several days under the same conditions. After 3 days, the only metabolite observed is triol (IIIc) (60%); after 7 days the triol yield reaches 67%.
- Example 6 The other half of the culture medium and the biomass of Example 6 is supplemented with terfenadine (10 mg in 0.5 ml ethanol) and incubated under the same conditions as in Example 6, for 3 days, then brought to pH 8.0 by addition of 7.5 M NaOH. Incubation is continued for 4 additional days and we get 16% triol-phosphate (IIIb), 37% fexofenadine (I) and 26% triol (IIIc).
- Preculture is carried out in a minimum medium (the carbon source is glucose) in 500 ml Erlenmeyer flasks containing 100 ml of sterile medium.
- the erlens are seeded with 450 ⁇ l of a glycerol suspension of Streptomyces platensis NRRL 2364 (stock frozen at -80 ° C) and incubated in an orbital shaker (2.5 cm off center) at 34 ° C, 250 RPM for 75 hours .
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
- procéder d'abord à l'incubation dans le milieu de culture initialement à un pH d'environ 6,5, sans contrôle du pH, ce qui conduit (en même temps que le pH évolue vers 8,0-8,5) à une transformation complète de la terfénadine en un mélange stationnaire stable de triol-phosphate (IIIb) et de fexofénadine (Fig. 2) (exemples 2 et 3), puis abaisser le pH à une valeur comprise entre 3,5 et 4 afin de favoriser la transformation de (IIIb) en (IIIc) et le laisser remonter lentement et spontanément vers 6,0, jusqu'à disparition complète du triol-phosphate (IIIb), puis réajuster et maintenir le pH aux environs de 8,0, jusqu'à transformation du triol (IIIc) en fexofénadine (Fig. 3) (exemple 4).
- procéder de la même manière à une incubation dans le milieu de culture, initialement à un pH d'environ 6,5, sans contrôle du pH, (le pH évolue naturellement vers 8,0-8,5) puis abaisser et maintenir celui-ci à une valeur comprise entre 6,0 et 6,5, pH auquel le triol-phosphate (IIIb) est assez rapidement hydrolysé, comme résultat de l'équilibre des activités phosphatase-phosphorylase à ce pH, tandis que le triol (IIIc) est lui-même assez rapidement oxydé, jusqu'à transformation presque complète en fexofénadine (fig. 4) (exemple 5).
- un procédé tel que défini plus haut dans lequel le pH
initialement à environ 6,5,
- évolue naturellement à 8,0-8,5, ce qui conduit à un mélange de triol-phosphate (IIIb) et de composé de formule (I),
- est ensuite abaissé à une valeur comprise entre 3,5 et 4 afin de favoriser la transformation du composé intermédiaire de formule (IIIb) en composé intermédiaire de formule (IIIc),
- puis évolue naturellement à environ 6,0 jusqu'à disparition complète du composé (IIIb),
- et enfin est réajusté et maintenu à environ 8,0 jusqu'à transformation du composé (IIIc) en Fexofénadine.
- un procédé tel que défini plus haut dans lequel le pH
initialement à environ 6,5
- évolue naturellement à 8,0-8,5,
- puis est abaissé et maintenu à une valeur comprise entre 6,3 et 6,8.
- un procédé tel que défini plus haut dans lequel au cours de l'étape de purification, l'extraction du produit de formule (I) est effectuée dans l'acétate d'éthyle.
la terfénadine (II) a un temps de rétention de 14,56 min., la terfénadine-P (IIIa), un temps de rétention de 11,8 min., le triol (IIIc), un temps de rétention de 9,61 min., la fexofénadine, un temps de rétention de 9,45 min. et le triol-P (IIIb), un temps de rétention de 7,43 min.
Métabolisation de la terfénadine par divers microorganismes, 0,2 g/l, 96 h, 27°C. | |||||
Terfénadine | Triol-P | Fexofénadine | Triol | Terfénadine-P | |
Absidia blakesleeana ATCC 6811 | + | - | - | - | - |
Absidia blakesleeana ATCC 42838 | - | ± | - | - | - |
Absidia blakesleeana ATCC 22617 | - | - | - | - | - |
Absidia blakesleeana ATCC 10148b | - | ± | - | - | - |
Absidia blakesleeana ATCC 22739 | - | ± | - | - | - |
Absidia corymbifera LCP 63.1800 | - | ± | +++ | + | - |
Absidia corymbifera LCP 64.1942 | - | - | ± | - | - |
Absidia corymbifera LCP 86.3480 | - | ± | ± | - | - |
Actinomucor elegans MMP 2092 | ± | + | ± | - | - |
Aspergillus ochraceus ATCC 1008 | - | - | ± | - | - |
Cunninghamella blakesleeana ATCC 8688a | ± | ± | - | ± | ± |
Cunninghamella echinulata LCP 73.2203 | ± | - | - | ± | - |
Cunninghamella echiniulata NRRL 3655 | ± | ± | - | ± | ± |
Cunninghamella elegans ATCC 9245 | ± | - | - | - | + |
Streptomyces platensis NRRL 2364 | - | - | + | +++ | - |
RMN 13C (CD3OD, 62,9 MHz) Δ, ppm : 23,7 (CH2, C-10), 27,1 (2 CH2, C-13), 30,2 (2 CH3, C-3), 39,0 (CH2, C-9), 44,9 (CH, C-14), 50,9 (C quat., C-2), 55,4 (2 CH2, C-12), 59,5 (CH2, C-11), 75,9 (CH, C-8), 81,7 (C quat., C-15), 23,7 (CH2, C-10), 128,6 ; 123,9 ; 129,4 et 131,0 (CH, C-5, C-6, C-17, C-18, C-19, C-20 et C-21), 145,2 ; 149,2 et 150,3 (C quat., C-4, C-7 et C-16), 186,3 (C quat., C-1).
MS (electrospray, ions négatifs), m/z : 500 (M-H+), 456 (M-H+-CO2) , 378 (456-C6H6).
Ce produit est purifié sur colonne de gel de silice (230-400 mesh, 40 g de silice, diamètre = 3 cm) en éluant avec le mélange chlorure de méthylène/méthanol/hydroxyde d'ammonium (82,5-15-2,5). On récupère 312 mg de fexofénadine pure (61,4 %).
- température régulée à 34°C
- agitation constante (pas de régulation de pO2)
- aération constante à 54 l/h (3vvm)
- pH régulé à 6.0 par ajout de KOH à 20%
Vitesse initiale d'oxydation de la Terfénadine en fonction du pH (Biomasse de 66 h, lavée et remise en suspension dans un tampon phosphate 0,05 M en présence de terfénadine 1061 µmol/litre). La mesure effectuée par HPLC correspond à la somme (triol + triol-phosphate + fexofénadine) | |
pH | Terfénadine oxydée (total) µmol/l/h |
6,3 | 1,60 |
6,5 | 2,45 |
7,0 | 0,60 |
7,5 | 0,59 |
8,0 | 0,76 |
Vitesse initiale (après 2 heures d'incubation) de phosphorylation du triol en fonction du pH (Biomasse de 66 h, lavée et remise en suspension dans un tampon phosphate 0,05 M en présence de triol 186 µmol/litre). On mesure par HPLC le triol-phosphate formé dans le surnageant d'incubation (aucune formation de fexofénadine n'est observée dans les 2 premières heures). | |
pH | Triol-phosphate µmol/l/h |
6,3 | 53,5 |
6,5 | 57,0 |
7,0 | 41,5 |
7,5 | 27,0 |
8,0 | 24,0 |
Vitesse initiale d'hydrolyse du triol-phosphate en fonction du pH (surnageant d'incubation de 120 heures contenant 272 µmol/litre de triol-phosphate, ajusté et maintenu aux différents pHs par HCl concentré et incubé à 27°C. L'hydrolyse est mesurée en HPLC à la fois par la disparition de triol-phosphate et l'apparition de triol. La vitesse initiale est calculée sur la moyenne des prélèvements effectués pendant les 7,5 premières heures d'hydrolyse. | |||||
Après 4 heures d'incubation | Après 24 heures d'incubation | Vitesse initiale d'hydrolyse du triol-phosphate µmol/l/h | |||
triol-phosphate résiduel µmol/l (% hydrolyse) | triol apparu µmol/l (% hydrolyse) | trial-phosphate résiduel µmol/l (% hydrolyse) | triol apparu µmol/l (% hydrolyse) | ||
4,0 | 258 (5 %) | 12 (4,4 %) | 223 (18 %) | 35 (13 %) | 3,13 |
5,0 | 234 (14 %) | 40 (14,7 %) | 148 (45,6%) | 120 (44,1%) | 8,71 |
6,0 | 196 (27,9%) | 68 (25 %) | 50 (81,7%) | 216 (79,4%) | 17,49 |
6,5 | 224 (17,6%) | 30 (11 %) | 140 (48,5%) | 131 (48,2%) | 8,71 |
7,0 | 237 (12, 9%) | 30 (11 %) | 167 (38,6%) | 109 (40 %) | 7,12 |
7,5 | 240 (12 %) | 31 (11,4 %) | 181 (33 %) | 77 (28,3 %) | 5,48 |
8,0 | 244 (10 %) | 19 (7 %) | 197 (28 %) | 69 (25,4 %) | 4,37 |
oxydation du triol mesurée entre 6 h et 24 h d'incubation en fonction du pH (Biomasse de 66 h, lavée et remise en suspension dans un tampon phosphate 0,05 M en présence de triol 186 µmol/litre). Dans cet intervalle de temps où la fexofénadine est formée, la concentration en triol est stationnaire. Les deux produits sont mesurés par HPLC. | |||
pH | Triol aux temps 6-24 h µmol/litre | Triol-phosphate aux temps 6-24 h µmol/litre | Fexofénadine apparue entre 6 et 24 h µmol/litre (%) |
6,3 | 110-130 | 65-27 | 0 (0) |
6,5 | 93-96 | 72-31 | 15 (15,6) |
7,0 | 46-58 | 110-64 | 25 (45,1) |
7,5 | 21-43 | 124-61 | 30 (69,7) |
8,0 0 | 20-49 | 128-41 | 30 (61, 2) |
Claims (9)
- Procédé de préparation des composés de formule (I) : caractérisé en ce qu'on effectue une bioconversion du ou des composés de formule (II) : avec soit une culture d'un microorganisme de genre Absidia corymbifera soit une culture d'un microorganisme de genre Streptomyces, à un pH compris entre 5,0 et 8,0, afin d'obtenir le ou les composés de formule (I) attendus, qui le cas échéant sont isolés, purifiés et/ou salifiés, les composés de formules (I) ou (II) pouvant être sous les deux formes énantiomères possibles, isolés ou en mélanges.
- Procédé selon la revendication 1 dans lequel l'Absidia corymbifera est Absidia corymbifera LCP 63-1800.
- Procédé selon la revendication 1 dans lequel le Streptomyces est Streptomyces platensis NRRL 2364.
- Procédé selon la revendication 1, 2 ou 3 dans lequel on effectue une bioconversion de la Terfénadine, correspondant à un mélange racémique des énantiomères de formule (II), afin d'obtenir la Fexofénadine, correspondant à un mélange racémique des énantiomères de formule (I).
- Procédé selon l'une quelconque des revendications 1 à 4 dans lequel les conditions de biotransformation sont les suivantes :concentration en Terfénadine ajoutée d'environ 0,5 à 10 g/lpH évoluant entre 5,0 et 8,0température comprise entre 26°C et 28°Caération par introduction d'un débit d'air d'environ 1 l/minute et par litre de bouillon de culture.
- Procédé selon l'une quelconque des revendications 1 à 5 dans lequel le pH initialement à environ 6,5,évolue naturellement à 8,0-8,5, ce qui conduit à un mélange de triol-phosphate (IIIb) : et de composé de formule (I),est ensuite abaissé à une valeur comprise entre 3,5 et 4 afin de favoriser la transformation du composé intermédiaire de formule (IIIb) en composé intermédiaire de formule (IIIc) :puis évolue naturellement à environ 6,0 jusqu'à disparition complète du composé (IIIb),et enfin est réajusté et maintenu à environ 8,0 jusqu'à transformation du composé (IIIc) en Fexofénadine.
- Procédé selon l'une quelconque des revendications 1 à 5 dans lequel le pH initialement à environ 6,5évolue naturellement à 8,0-8,5,puis est abaissé et maintenu à une valeur comprise entre 6,3 et 6,8.
- Procédé selon l'une quelconque des revendications précédentes caractérisé en ce que, au cours de l'étape de purification, l'extraction du produit de formule (I) tel que défini à la revendication 1, est effectuée dans l'acétate d'éthyle.
- A titre de composé intermédiaire le composé de formule (IIIc) telle que définie à la revendication 6.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9803349 | 1998-03-19 | ||
FR9803349A FR2776302B1 (fr) | 1998-03-19 | 1998-03-19 | Nouveau procede de preparation de la fexofenadine |
PCT/FR1999/000625 WO1999047693A1 (fr) | 1998-03-19 | 1999-03-18 | Nouveau procede de preparation de la fexofenadine |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1062358A1 EP1062358A1 (fr) | 2000-12-27 |
EP1062358B1 true EP1062358B1 (fr) | 2003-06-04 |
Family
ID=9524214
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99909036A Expired - Lifetime EP1062358B1 (fr) | 1998-03-19 | 1999-03-18 | Nouveau procede de preparation de la fexofenadine |
Country Status (15)
Country | Link |
---|---|
US (2) | US6558931B1 (fr) |
EP (1) | EP1062358B1 (fr) |
JP (1) | JP4291511B2 (fr) |
AR (1) | AR014738A1 (fr) |
AT (1) | ATE242333T1 (fr) |
AU (1) | AU2842799A (fr) |
DE (1) | DE69908569T2 (fr) |
DK (1) | DK1062358T3 (fr) |
DZ (1) | DZ2746A1 (fr) |
ES (1) | ES2196783T3 (fr) |
FR (1) | FR2776302B1 (fr) |
MA (1) | MA26615A1 (fr) |
PT (1) | PT1062358E (fr) |
TN (1) | TNSN99042A1 (fr) |
WO (1) | WO1999047693A1 (fr) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2776302B1 (fr) * | 1998-03-19 | 2002-04-12 | Hoechst Marion Roussel Inc | Nouveau procede de preparation de la fexofenadine |
GB0013368D0 (en) * | 2000-05-31 | 2000-07-26 | Pfizer Ltd | Enzymatic oxidations |
US6610518B2 (en) | 2000-05-31 | 2003-08-26 | Pfizer Inc. | Enzymatic oxidations |
US6613906B1 (en) | 2000-06-06 | 2003-09-02 | Geneva Pharmaceuticals, Inc. | Crystal modification |
GB0018691D0 (en) * | 2000-07-28 | 2000-09-20 | Rolabo Sl | Process |
US6613907B2 (en) | 2000-11-08 | 2003-09-02 | Amr Technology, Inc. | Process for the production of piperidine derivatives with microorganisms |
AU2003209673B2 (en) * | 2002-03-08 | 2007-10-18 | M/S. Ind-Swift Limited | Tasteless directly compressible fast-dissolving complexes and pharmaceutical formulations thereof |
US20090076080A1 (en) * | 2007-09-19 | 2009-03-19 | Protia, Llc | Deuterium-enriched fexofenadine |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE230395T1 (de) * | 1993-06-25 | 2003-01-15 | Merrell Pharma Inc | Neue zwischenprodukte für die herstellung von antihistaminschen 4- diphenylmethyl/diphenylmethoxypiperidin-derivat n |
US6147216A (en) * | 1993-06-25 | 2000-11-14 | Merrell Pharmaceuticals Inc. | Intermediates useful for the preparation of antihistaminic piperidine derivatives |
ATE260983T1 (de) * | 1997-03-11 | 2004-03-15 | Aventis Pharma Inc | Verfahren zur herstellung von 4-(4-(4- (hydroxydiphenyl)-1-piperidinyl)-1-hydroxybutyl - alpha,alpha-dimenthylphenylessigsäure und phosphorylierter derivate |
FR2776302B1 (fr) * | 1998-03-19 | 2002-04-12 | Hoechst Marion Roussel Inc | Nouveau procede de preparation de la fexofenadine |
-
1998
- 1998-03-19 FR FR9803349A patent/FR2776302B1/fr not_active Expired - Lifetime
-
1999
- 1999-03-17 DZ DZ990047A patent/DZ2746A1/fr active
- 1999-03-17 MA MA25501A patent/MA26615A1/fr unknown
- 1999-03-17 AR ARP990101165A patent/AR014738A1/es unknown
- 1999-03-18 ES ES99909036T patent/ES2196783T3/es not_active Expired - Lifetime
- 1999-03-18 PT PT99909036T patent/PT1062358E/pt unknown
- 1999-03-18 JP JP2000536876A patent/JP4291511B2/ja not_active Expired - Lifetime
- 1999-03-18 DK DK99909036T patent/DK1062358T3/da active
- 1999-03-18 US US09/646,517 patent/US6558931B1/en not_active Expired - Lifetime
- 1999-03-18 TN TNTNSN99042A patent/TNSN99042A1/fr unknown
- 1999-03-18 AT AT99909036T patent/ATE242333T1/de active
- 1999-03-18 WO PCT/FR1999/000625 patent/WO1999047693A1/fr active IP Right Grant
- 1999-03-18 EP EP99909036A patent/EP1062358B1/fr not_active Expired - Lifetime
- 1999-03-18 AU AU28427/99A patent/AU2842799A/en not_active Abandoned
- 1999-03-18 DE DE69908569T patent/DE69908569T2/de not_active Expired - Lifetime
-
2003
- 2003-03-20 US US10/392,699 patent/US7241601B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
FR2776302A1 (fr) | 1999-09-24 |
WO1999047693A1 (fr) | 1999-09-23 |
DK1062358T3 (da) | 2003-09-29 |
US7241601B2 (en) | 2007-07-10 |
AR014738A1 (es) | 2001-03-28 |
FR2776302B1 (fr) | 2002-04-12 |
JP2002506653A (ja) | 2002-03-05 |
US20060019358A1 (en) | 2006-01-26 |
JP4291511B2 (ja) | 2009-07-08 |
EP1062358A1 (fr) | 2000-12-27 |
MA26615A1 (fr) | 2004-12-20 |
US6558931B1 (en) | 2003-05-06 |
DE69908569D1 (de) | 2003-07-10 |
ES2196783T3 (es) | 2003-12-16 |
TNSN99042A1 (fr) | 2005-11-10 |
DE69908569T2 (de) | 2004-05-13 |
AU2842799A (en) | 1999-10-11 |
PT1062358E (pt) | 2003-10-31 |
ATE242333T1 (de) | 2003-06-15 |
DZ2746A1 (fr) | 2003-09-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4410629A (en) | ML-236B Derivatives and their preparation | |
FR2516935A1 (fr) | Procede de preparation de derives de 3-hydroxy-ml-236b connus comme m-4 et m-4' | |
US6001615A (en) | Enzymatic reduction of ketone groups in 6-cyano-3,5-dihydroxy-hexanoic alkyl ester | |
EP1062358B1 (fr) | Nouveau procede de preparation de la fexofenadine | |
HU211052B (en) | Method for preparing 2-aryl-propionic acids in stereo-specific form, pharmaceutical compositions containing them and microorganisms for preparation | |
JP3333206B2 (ja) | 不斉還元方法 | |
US4104282A (en) | Novel 3-(oxygenated alkyl)-1,9-dihydroxy and 1-hydroxy-9-keto dibenzo[b,d]py | |
RU2235784C2 (ru) | Стереоизбирательное микробное восстановление рацемического тетралона (его варианты) | |
EP0599967B1 (fr) | Resolution de l'acide arylalcanoique | |
EP0231234B1 (fr) | Procede d'hydroxylation par voie microbiologique de la quinine, de la quinidine, et de derives | |
US5258290A (en) | Fermentation process for the production of β-carboline derivatives by Myrothecium verrucaria | |
US5459067A (en) | Method for producing optically active norborneol by ester hydrolysis | |
NO172903B (no) | Fremgangsmaate for fremstilling av optisk aktive (+)-bicyklo(3.3.0)oktanol-derivater | |
FR2466505A1 (fr) | Procede de production d'acide 2,5-dicetogluconique | |
JPS6225357B2 (fr) | ||
KR100186706B1 (ko) | 프라바스타틴 나트륨의 제조방법 | |
JPH04321698A (ja) | 生理活性物質m6124及びその製造方法 | |
JPS5945360B2 (ja) | 生理活性物質ml−236bの製造法 | |
JP2004531246A (ja) | ヒト血小板凝集および大豆リポキシゲナーゼの阻害剤の製造方法 | |
WO2003004666A2 (fr) | Procede de reduction enantioselectif d'une cetone aromatique prochirale comprenant au moins un groupe trifluoromethyle sur le cycle aromatique | |
JP2002523107A (ja) | (2r)−ピペリジン誘導体の製造方法 | |
EP0828848A1 (fr) | Preparation de composes hydroxy par bioconversion a l'aide de dioxygenase | |
JP2000279190A (ja) | 光学活性3−置換(2−ヒドロキシアルキル)インドールの製造方法 | |
JP2000262295A (ja) | 光学活性3−置換インドールの製造方法 | |
JPH05211880A (ja) | 酵素法による光学活性体の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20001019 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: AVENTIS PHARMA S.A. |
|
17Q | First examination report despatched |
Effective date: 20010706 |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D Free format text: NOT ENGLISH |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: FRENCH |
|
REF | Corresponds to: |
Ref document number: 69908569 Country of ref document: DE Date of ref document: 20030710 Kind code of ref document: P |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20030402366 Country of ref document: GR |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: A. BRAUN, BRAUN, H?RITIER, ESCHMANN AG PATENTANWAE |
|
GBT | Gb: translation of ep patent filed (gb section 77(6)(a)/1977) |
Effective date: 20030804 |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2196783 Country of ref document: ES Kind code of ref document: T3 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20040305 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PFA Owner name: AVENTIS PHARMA S.A. Free format text: AVENTIS PHARMA S.A.#20, AVENUE RAYMOND ARON#92160 ANTONY (FR) -TRANSFER TO- AVENTIS PHARMA S.A.#20, AVENUE RAYMOND ARON#92160 ANTONY (FR) |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PCAR Free format text: NEW ADDRESS: HOLBEINSTRASSE 36-38, 4051 BASEL (CH) |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 18 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 19 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20171227 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20180314 Year of fee payment: 20 Ref country code: LU Payment date: 20180226 Year of fee payment: 20 Ref country code: DE Payment date: 20180306 Year of fee payment: 20 Ref country code: NL Payment date: 20180314 Year of fee payment: 20 Ref country code: DK Payment date: 20180312 Year of fee payment: 20 Ref country code: FI Payment date: 20180312 Year of fee payment: 20 Ref country code: GB Payment date: 20180314 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: PT Payment date: 20180319 Year of fee payment: 20 Ref country code: GR Payment date: 20180214 Year of fee payment: 20 Ref country code: SE Payment date: 20180313 Year of fee payment: 20 Ref country code: IE Payment date: 20180312 Year of fee payment: 20 Ref country code: AT Payment date: 20180226 Year of fee payment: 20 Ref country code: FR Payment date: 20180223 Year of fee payment: 20 Ref country code: IT Payment date: 20180321 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20180402 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CY Payment date: 20180312 Year of fee payment: 20 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R071 Ref document number: 69908569 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MK Effective date: 20190317 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EUP Effective date: 20190318 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20190317 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MK9A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20190317 Ref country code: IE Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20190318 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MK Effective date: 20190318 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK07 Ref document number: 242333 Country of ref document: AT Kind code of ref document: T Effective date: 20190318 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20190326 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20200723 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20190319 |